Resorbable interbody spinal fusion devices

ABSTRACT

A resorbable interbody fusion device for use in spinal fixation is disclosed. The device is composed of  25 - 100 % bioresorbable or resorbable material. The interbody fusion device of the invention can be in any convenient form, such as a wedge, screw or cage. Preferably, the resorbable device of the invention is in the shape of a tapered wedge or cone, which further desirably incorporates structural features such as serrations or threads better to anchor the device in the adjoining vertebrae. The preferred device further comprises a plurality of peripheral voids and more desirably a central void space therein, which may desirably be filled with a grafting material for facilitating bony development and/or spinal fusion, such as an autologous grafting material. As the preferred material from which the resorbable interbody fusion device is manufactured is most likely to be a polymer that can produce acidic products upon hydrolytic degradation, the device preferably further includes a neutralization compound, or buffer, in sufficiently high concentration to decrease the rate of pH change as the device degrades, in order to prevent sterile abscess formation caused by the accumulation of unbuffered acidic products in the area of the implant.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from U.S. patent applicationSer. No. 09/131,716, filed Aug. 10, 1998; and from U.S. ProvisionalPatent Application No. 60/055,291, filed Aug. 13, 1997; Ser. No.60/074,076, filed Feb. 9, 1998; Ser. No. 60/074,197, filed Feb. 10,1998, and Ser. No. 60/081,803, filed Apr. 15, 1998, the entiredisclosures of which are incorporated herein by reference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] Not applicable

BACKGROUND OF THE INVENTION

[0003] The present invention relates to the field of interbody spinalfusion devices.

[0004] In the structure of the spine of vertebrates including humans,the space between adjacent vertebrae is referred to as the interbodyspace. In normal spines, this space is occupied by the structurecommonly referred to as a disc. This intervertebral structure separatesand cushions the vertebrae.

[0005] Various pathologic and traumatic conditions require excision of aspinal disc and stabilization of the superior and inferior vertebraewhile bony fusion develops. In 1995, approximately 225,000 new spinalfusions were performed in the United States alone, and of these aboutone half were performed in the thoracic and cervical spine, with theremaining spinal fusions focused on the lumbar spine. To stabilize thespine where the surgery has occurred, an internal fixation device isfrequently used. Such implants provide the ability to improve spinalalignment and maintain the developing alignment while fusion develops.Fixation of the spine can further correct deformity and provideimmediate stability, thereby facilitating spinal fusion, earlymobilization, and, when necessary, entry into rehabilitative programs.

[0006] The use of fixation devices is beneficial in several ways. First,the avoidance of long-term bed rest, thought by many to decreasenon-neurological morbidity, is achieved. Additionally, fixation devicesare thought to promote fracture healing and therefore reduce the needfor rigid and cumbersome post-operative bracing.

[0007] While a number of commercially available implants for spinalstabilization are known, these devices are not resorbable and therefore,remain permanently at the implant site. Meticulous bone preparation andgrafting is essential for successful long-term stability using currentdevices. Metallic and graphite implants have been known to fatigue andwill eventually fail if the desired solid bony fusion is not achieved.Thus, it would be advantageous to obtain successful bony fusion andspinal development while avoiding the use of devices having theaforementioned drawbacks.

SUMMARY OF THE INVENTION

[0008] The present invention is directed to resorbable interbody fusiondevices for use as spacers in spinal fixation, wherein the device iscomposed of 25-100% bioresorbable or resorbable material. The devicescan be in any convenient form, such as a wedge, screw or cage. In oneembodiment, the interbody fusion device of the invention furtherdesirably incorporates structural features such as serrations to betteranchor the device in the adjoining vertebrae. In another embodiment, thedevice comprises a plurality of peripheral voids and more desirably acentral void space therein, which may desirably be filled with agrafting material for facilitating bony development and/or spinalfusion, such as an autologous grafting material. In addition, voidspaces increase the surface area of the device, thereby providingmultiple sites for resorption to occur.

[0009] In yet another embodiment, the interbody fusion device of theinvention further includes reinforcing fibers to enhance the structuralproperties thereof. These fibers may be made of the same polymericmaterial as the resorbable material from which the interbody fusiondevice is made, from a neutralization compound or, alternatively, fromanother biocompatible polymer, which may be crosslinked with a suitablecrosslinking agent to yield an interpenetrating network for increasedstrength and stability. In another alternative embodiment, thereinforcing fibers are incorporated into the device, e.g., during themolding process, being placed in the mold under tension and releasedafter the process of molding is complete.

[0010] Bioerodible polymers that are useful in the invention includepolydioxanone, poly(ε-caprolactone); polyanhydride; poly(ortho ester);copoly(ether-ester); polyamide; polylactone; poly(propylene fumarate)(H[—O—CH(CH₃)—CH₂—O—CO—CH═CH—CO—]_(n)OH); and combinations thereof. In apreferred embodiment, the polymer poly(lactide-co-glycolide) (PLGA: H[—OCHR—CO—]_(n)OH, R═H, CH₃), with a lactide to glycolide ratio in therange of 0:100% to 100:0% inclusive, is used.

[0011] As many of the preferred bioerodible polymers from which theresorbable interbody fusion device is manufactured are polymers that canproduce acidic products upon hydrolytic degradation, the devicepreferably further includes a neutralization compound, or buffer. Theneutralization compound is included in sufficiently high concentrationto decrease the rate of pH change as the device degrades, in order toprevent sterile abscess formation caused by the accumulation ofunbuffered acidic products in the area of the implant. Most preferably,the buffering or neutralizing agent is selected from a group ofcompounds wherein the pKa of the conjugate acids of the buffering orneutralization compound is greater than the pKa of the acids produced byhydrolysis of the polymers from which the device is prepared.

[0012] The neutralization compound, or buffer, included in thebioerodible material of the invention may be any base, base-containingmaterial or base-generating material that is capable of reacting withthe acidic products generated upon hydrolysis of the bioerodiblepolymer. Polymeric buffers which preferably include basic groups whichneutralize the acidic degradation products may also be used as bufferingcompounds. Another class of useful buffering compounds are those which,on exposure to water, hydrolyze to form a base as one reaction product.

[0013] In another alternative embodiment, the resorbable interbodyfusion device of the invention preferably includes a biological growthfactor, e.g., bone morphogenic protein, to enhance bone cell growth. Toprotect the growth factor and to provide for controlled delivery, thebiological growth factor may itself be compounded with a resorbablepolymer in some of the many techniques available and prepared as agrowth factor/polymer composite in pellet form, in small particle formor within the interstices or pores of a polymeric foam or low-densitypolymer and this polymer/growth factor composite is deposited into voidspaces of the resorbable spinal fusion device. Alternatively, the growthfactor, or protected growth factor, may simply be directly incorporatedinto the component formulation of the resorbable spinal fusion device.

[0014] Active periosteum cells may also be incorporated into a foam,e.g., deposited into void spaces of the resorbable spinal fusion device,in order to facilitate bone cell fusion. Further, the resorbable spinalfusion device of the invention may be prepared in such a manner as toexhibit a piezoelectric effect, to enhance bone wound healing.

[0015] As used herein, the terms “resorbable” and “bioresorbable” aredefined as the biologic elimination of the products of degradation bymetabolism and/or excretion and the term “bioerodible” is defined as thesusceptibility of a biomaterial to degradation over time, usuallymonths. The terms “neutralization compound” or “buffer” are defined asany material that limits or moderates the rate of change of the pH inthe implant and its near environment upon exposure to acid or base. Theterm “acidic products” is defined herein as any product that generatesan aqueous solution with a pH less than 7.

DESCRIPTION OF THE DRAWINGS

[0016] The invention will be more fully understood from the followingdetailed description taken in conjunction with the accompanying drawingsin which:

[0017]FIGS. 1A, 1B and 1C are perspective top, side and front views,respectively, of an interbody spinal fusion device according to thepresent invention;

[0018]FIGS. 2A, 2B and 2C are top, side and perspective views,respectively, of another embodiment of an interbody spinal fusion deviceof the invention;

[0019]FIGS. 3A, 3B and 3C are top, side and perspective views,respectively, of another embodiment of an interbody spinal fusion deviceof the invention;

[0020]FIGS. 4A and 4B are side and top views, respectively, of anotherembodiment of an interbody spinal fusion device of the invention;

[0021]FIGS. 5A and 5B are side and top views, respectively, of anotherembodiment of an interbody spinal fusion device of the invention;

[0022]FIG. 6A is a perspective view of a mold and ram assembly forpreparing an interbody spinal fusion device of the invention;

[0023]FIGS. 6B and 6C are edge and plan views, respectively, of thefront face plate of the mold of FIG. 6A;

[0024]FIG. 6D shows a disc with serrated slots for use in the mold ofFIG. 6A;

[0025]FIGS. 6E and 6F are front and side views, respectively, of athreaded tension tube used with the mold of FIG. 6A;

[0026]FIG. 6G is a section through a mold assembly fitted withreinforcing fibers and associated holder assemblies;

[0027]FIG. 7 is a plot of displacement versus load for an interbodyspinal fusion device of the invention; and

[0028]FIG. 8 shows compression strength with load for interbody spinalfusion devices of the invention with and without the incorporation of abuffering or neutralizing compound.

DETAILED DESCRIPTION OF THE INVENTION

[0029] The present invention provides, in one embodiment, an interbodyspinal fusion device (IFD) comprising a resorbable spinal wedge forvertebral spacing as an adjunct to spinal fusion. Made from abiodegradable, biocompatible polymer, preferablypoly(lactic-co-glycolic) acid (PLGA), discussed further below, thisresorbable spacer incorporates peripheral voids and central voids, whichcan be filled with autologous grafting material to facilitate bonydevelopment and spinal fusion, and serrated or threaded faces tostabilize and align vertebral bodies. The spinal fusion device of theinvention is used as an adjunct to fusions of the cervical, thoracic orlumbar vertebrae, the configuration and dimensions of the devicedepending on the site of use.

[0030] A preferred embodiment of a spinal implant, fabricated from abiocompatible and biodegradable polyester and intended to replace acervical disc, C4, 5, or 6, is shown in FIGS. 1A, 1B and 1C. A rodmolded from a suitable material, as described below, is machined to thedesired configuration and dimensions. Relatively complex geometries canbe readily fabricated in this manner. Suitable biocompatible extraneousmaterials such as plasticizers or other machining aids, can be includedin the material if desired.

[0031] As shown in FIG. 1A, a preferred resorbable interbody spinalfusion device of the invention 10 is in the shape of a tapered wedge,having a top face 11, a bottom face 12, side faces 13, a front end 14and a back end 15. The surfaces of top and bottom faces 11 and 12 eachhave serrations 16 to aid in anchoring the device to the surroundingbone. Wedge 10 preferably contains holes 17 of convenient diameter,which may be drilled through the wedge to facilitate resorption of thepolymer from which the device has been made. A plurality of channels orports 18 through the wedge or a larger center hole 19 in the wedge areuseful for the introduction of autologous bone. As illustrated in FIGS.1B and 1C, the spinal wedge is preferably machined to have a taper fromback end 15 to front end 14, such that the front end 14 is narrower thanthe back end 15.

[0032] In another embodiment, as shown in FIGS. 2A-2C resorbable spinalfusion device 20 is shaped like a tapered rod having ridges 22 withthreads 21. Device 20 functions as a screw and contains a cylindricalaxially extending hole 23 and slots 24 to facilitate screwing the deviceinto the spine of the patient. The device also contains recesses 26between ridges 22 to facilitate ingrowth of tissue that would aid inanchoring the device in place.

[0033] As shown in FIGS. 3A-3C, in a further embodiment, the device 30is of cruciform shape having arms 33. Threads 31 extend the length ofthe outer surfaces of arms 33. In another embodiment, shown in FIGS.4A-4B, the device is shaped like a threaded screw having a continuousthread 41 provided around the surface of the tapered body. Cylindricalholes 43 and 44 are provided through the body, the holes beingorthogonal to each other and to screw axis 42. A cylindrical hole 45 isprovided coaxially with axis 42. Slots 46 in the top 48 serve toposition and retain a tool that can be used to screw the device intoplace.

[0034] As shown in FIGS. 5A and 5B, a further embodiment of a threadedscrew contains flat side areas 52 alternating with threaded corner areas51. Slots 53 can be machined or otherwise provided in the flat areas, tofacilitate ingrowth of tissue, and can be of a constant width or can betapered. A slot 56 in top 58 of the device accommodates a suitable toolto facilitate insertion.

[0035] For replacement of one of the cervical discs C4, C5, or C6, thedevice shown in FIGS. 1A-1C preferably measures 15 mm laterally by 12 mmsagittally. The flattened side, positioned posterially, is 6-8 mm thick,enlarging to about 7-9 mm at the anterior edge; thus the device has ataper of approximately 4.8 degrees. Both surfaces are serrated, theserrations directed laterally. The serrations may be either square cutor cut at an angle with one face vertical and the other sloping upwardanteriorly.

[0036] The thickness of the device of the invention will govern the rateat which it degrades and total degradation time. Thus, interbody spinalfusion devices can be prepared with multiple thicknesses, but all havingthe same approximately 5° taper. For example, the anterior thicknesscould range from 7 to 9 mm and the posterior thickness from 6 to 8 mm.The taper provides the correct orientation to the vertebrae with whichthe device is in contact and can also serve to keep the device in place.

[0037] The vertebral body is a fairly cylindrical mass consisting ofcancellous bone surrounded by a thin layer of cortical bone. Thus, themechanical properties of the device should preferably match those of thecancellous bone of the vertebrae in regard to proportional limit stress,compression at proportional limit, modulus of elasticity, failure stressand compression at failure (See, e.g., Lindahl, Acta Orthop. Scand.47:11, 1976; Hansson et al., Spine 12:56, 1987).

[0038] Bioerodible polymers that are useful in the spinal fusion deviceof the invention include polydioxanone, poly(E-caprolactone);polyanhydride; poly(ortho ester); copoly(ether-ester); polyamide;polylactone; poly(propylenefumarate)(H[—O—CH(CH₃)—CH₂—O—CO—CH═CH—CO—]_(n)OH); poly(lactic acid);poly(glycolyic acid); poly(lactide-co-glycolide); and combinationsthereof. Selection of a particular polymer is based primarily on theknown properties of the polymer, such as the potentiality forcross-linking, polymer strength and moduli, rate of hydrolyticdegradation, etc. One of ordinary skill in the art may take these and/orother properties into account in selecting a particular polymer for aparticular application. Thus, the selection of a particular polymer iswithin the skills of the ordinary skilled practitioner.

[0039] In a preferred embodiment, the polymer poly(lactide-co-glycolide)(H[—OCHR—CO—]_(n)OH, R═H, CH₃) (PLGA) is used. The PLGA polymers usedaccording to the invention desirably have a lactide to glycolide ratioin the range of 0:100% to 100:0%, inclusive, i.e., the PLGA polymer canconsist of 100% L- or D,L-lactide (PLA), 100% glycolide (PGA), or anycombination of lactide and glycolide residues. These polymers have theproperty of degrading hydrolytically in vivo to form organic acids(lactic acid and glycolic acid) which accumulate in the regionsurrounding the implant. These acids are metabolized and eventuallyexcreted as carbon dioxide and water or enter the citric acid cycle.

[0040] The process by which alpha polyesters such as PLA, PGA, and PLGAbiodegrade is primarily by non-specific hydrolytic scission of the esterbonds. The L-lactic acid that is generated when PLA or PLGA degradesbecomes incorporated into the tricarboxylic acid cycle and is excretedfrom the lungs as carbon dioxide and water. Glycolic acid, produced bothby random hydrolytic scission and by enzymatically mediated hydrolysis,may be excreted in the urine and also can enter the TCA cycle andeventually be oxidized to carbon dioxide and water (Hollinger et al.,Clin. Orthop. Rel. Res. 207: 290-305, 1986).

[0041] A particularly preferred polymer for use in the device of theinvention is poly(d,l-lactide-co-glycolide)-85:15 (Boehringer-Ingelheim:distributor, Henley Chemicals, Inc., Montvale, N.J.), the 85:15designation referring to the lactide to glycolide mole ratio. Theparticularly preferred polymer is Resomer™ RG 858, with an inherentviscosity of approximately 1.4 corresponding to a weight averagemolecular weight of 232,000 as measured by gel permeation chromatography(GPC).

[0042] The polymer can be used as received or purified by precipitationfrom tetrahydrofuran solution into isopropanol, air dried and thenexhaustively vacuum dried. Polymer data (composition and molecularweight) can be confirmed by nuclear magnetic resonance and by GPC (Hsuet al., J. Biomed. Mater. Res. 35:107-116, 1997).

[0043] Spinal fusions require interbody fusion devices that willmaintain significant structural rigidity for 6-12 months. Strengthrequirements depend on the location of the disc to be replaced. When aperson is standing, the forces to which a disc is subjected are muchgreater than the weight of the portion of the body above it. Nachemsonet al. (Acta. Orthop. Scand. 37:177, 1966; J. Bone Joint Surgery46:1077, 1964; Clin. Orthop. 45:107, 1966) has determined that the forceon a lumbar disc in a sitting position is more than three times theweight of the trunk. Daniels et al. (J. Appl. Biomater. 1:57-78, 1990)have reviewed much of the mechanical data of PGA, PLA, and PLGA.

[0044] As a bioerodible polymer undergoes hydrolysis in the body, anyacidic degradation products formed may be implicated in irritation,inflammation, and swelling (sterile abscess formation) in the treatedarea. To counteract this effect, a neutralization compound, or buffer,is desirably included in the bioerodible material to neutralize theacidic degradation products and thereby reduce the sterile abscessreaction, as described in copending U.S. application Ser. No.08/626,521, filed Apr. 3, 1996, the whole of which is herebyincorporated by reference herein.

[0045] The buffering compound included in the bioerodible material ofthe invention may be any base, base-containing or base-generatingmaterial that is capable of reacting with the acidic products generatedupon hydrolysis of the bioerodible polymer. Exemplary bufferingmaterials include salts of inorganic or organic acids, salts ofpolymeric organic acids or polymeric bases such as polyamines.Preferably calcium salts of weak acids such as, e.g., tribasic calciumphosphate, dibasic calcium phosphate, or calcium carbonate are use. Tobe useful, the conjugate acids from which the buffering materials arederived must have a pKa greater than those of L-lactic acid (pKa=3.79),D, L-lactic acid (pKa=3.86), or glycolic acid (pKa=3.83), if a PLGA isthe polymer which is undergoing hydrolysis. Thus, for example, salts ofacetic acid (pKa=4.74), or succinic acid (pK₁=4.19, pK₂=5.64) may alsobe used.

[0046] Buffer compositions of lower solubility are preferred becausebuffer loss from the polymer by diffusion will be slower (Gresser andSanderson, “Basis for Design of biodegradable Polymers for SustainedRelease of Biologically Active Agents” in Biopolymeric ControlledRelease Systems, Ch. 8, D. L. Wise, Ed., CRC Press, 1984). Preferably,the buffering compound has an acid dissociation constant that is smallerthan the acid dissociation constant of the acidic products generatedupon hydrolysis of the bioerodible polymer. Ionic buffers will, ingeneral, be the salts of weak acids. The acid, of which the buffer is asalt, should have an ionization constant (acid dissociation constant,K_(a)) which is less than the K_(a) for the acid products of polymerhydrolysis. Alternatively, the buffering compound has a hydrolysisconstant that is greater than the hydrolysis constant of the acidicproducts.

[0047] Hydroxyapatite (HA) and calcium carbonate (CC) were eachinvestigated as buffering fillers. Results demonstrate that theinclusion of CC or HA in a, e.g., PLGA fixture can effectively moderatethe rate of pH decline as the fixture degrades. Further, the rapiddecline in pH can be offset without considering 100% neutralization ofthe lactic and glycolic components. Thus, even given that the polymericfixture will be filled with an inorganic buffer, the mechanicalcharacteristics of the fixture can be stabilized since the loadingrequirements for the buffer will not be nearly as compromising asexpected at the outset.

[0048] While both CC and HA can ameliorate the rate of decline in pH inthe region of polymer hydrolysis, the use of hydroxyapatite as a filleralso supports osteoconductivity. Thus, HA not only promotes bonyingrowth and obviates loosening of the fixture, but also acts as abuffer thereby preventing the formation of sterile abscesses that havebeen attributed to the acidic degradative products of PLGA implants. Theresulting resorbable fixture should be capable of a buffered hydrolyticdegradation and induction of bony ingrowth as resorption of the implantprogresses. A resorbable buffered bone fixture with such propertiescould provide structural support to stabilize and support a spinalrepair over the period of time required for natural healing to occur.

[0049] According to the invention a preferred buffering compound ishydroxyapatite. The formula Ca₁₀(OH)₂(PO₄)₆ may be written asCa(OH)₂.3Ca₃(PO₄)₂. When written in this manner it is seen that thefollowing neutralization reactions may be written:

2RCO₂H+Ca(OH)₂.3Ca₃(PO₄)₂→2RCO₂ ⁻+Ca⁺²+2H₂O+3Ca₃(PO₄)₂12RCO₂H+3Ca₃(PO₄)₂→6H₂PO₄ ⁻+9Ca⁺²+12RCO₂ ⁻

[0050] The dissociation constant of water (the conjugate acid of thehydroxyl ion) is K_(w)=10⁻¹⁴. The basic phosphate ion, PO₄ ⁻³, canneutralize two protons forming the following acids, for whichdissociation constants are given:

RCO₂H+PO₄ ⁻³→RCO₂ ⁻+HPO₄ ⁻²

RCO₂H+HPO₄ ⁻²→RCO₂ ⁻+H₂PO₄

K₂ of H₂PO₄ ⁻¹=6.2×10⁻⁸

K₃ of HPO₄ ⁻²4.2×10⁻¹³

[0051] Buffers included in the polymer in solid form preferably have arelatively small particle size, for example, between less than 1.0 and250 μm. Particle size reduction can be accomplished by any standardmeans known in the art, such as ball milling, hammer milling, airmilling, etc. If buffer and polymer are to be blended by the dry mixingmethod (described below), the polymer particle size must also beconsidered. Polymers such as the PLGAs have relatively low glasstransition temperatures and melting temperatures. Thus, polymer particlesize reduction must be accompanied by cooling, for example using aTekmar A-10 mill with a cryogenic attachment.

[0052] Following milling, the desired particle size range of the bufferand the polymer may be recovered by sieving through, for example, U.S.Standard sieves. Particles in the size ranges of <45, 45-90, 90-125,125-180, 180-250 μm may be conveniently isolated.

[0053] In selection of particle size range, it is sometimes desirable tocombine two or more ranges, or to use a wide range of sizes, forinstance all sizes less than 250 μm. Larger particles may be preferredin some applications of the invention because larger particles takelonger to be eroded by the acids and will therefore extend the usefullifetime of the buffer. In some cases particle size reduction will notbe necessary, such as when commercially available precipitated calciumcarbonate is used (e.g., Fisher Scientific, Inc., Catalog No. C-63).

[0054] The effectiveness of substances such as calcium carbonate andhydroxyapatite in neutralizing the acid products of polymer hydrolysisdepends not only on the quantity of the substance in the matrix, butalso on particle size and distribution, total surface area in contactwith the polymer, and solubility.

[0055] The presence of calcium ions in the buffered device hasadvantages with respect to the physical properties of the device as itundergoes erosion. It has been shown that calcium ions form ionicbridges between carboxylate terminal polymer chains (Domb et al., J.Polymer Sci. A28, 973-985 (1990); U.S. Pat. No. 4,888,413 to Domb).Calcium ion bridges between carboxylate anions increase the strength ofthe composite in which the polymer chains are terminated by carboxylateanion end groups over similar chains terminated by the hydroxyl groupsof, e.g., terminal glycol moieties or terminal a-hydroxy acids. In ananalogous manner, the polyesters comprising the family of PLGA's areexpected to be strengthened by calcium bridges between carboxylate anionterminated chains. As shown in FIG. 8 PLGA-85:15 wedges reinforced with40% HA showed an increase in compressive strength of approximately 5%over the nonreinforced controls.

[0056] Another class of useful buffering compounds are those which, onexposure to water, hydrolyze to form a base as one reaction product. Thegenerated base is free to neutralize the acidic products produced uponhydrolysis of the bioerodible polymer. Compounds of this type includearyl or alkyl carbamic acids and imines. These “basegeneratingcompounds” offer the advantage that the rate of hydrolysis of the basegenerator may be selected to correlate to the rate of hydrolysis of thebioerodible polymer.

[0057] Necessarily, the conjugate acid of the buffering compound has anacid dissociation constant that is smaller than the acid dissociationconstant of the acidic products generated upon hydrolysis of thebioerodible polymer. Alternatively, the buffering compound preferablyhas a hydrolysis constant that is greater than the hydrolysis constantof the acidic products.

[0058] Furthermore, the buffering compound preferably is only partiallysoluble in an aqueous medium. In general, buffers of lower solubilityare preferred because buffer loss from the polymer by diffusion will beminimized (Gresser and Sanderson, supra). The quantity of buffer toinclude depends on the extent of neutralization desired. This may becalculated as shown below, using a PLGA of any composition buffered withcalcium carbonate as an example.

[0059] The average residue molecular weight, RMW, for a PLGA is given by

RMW=14.03x+58.04

[0060] where x=mole fraction of lactide in the PLGA. The term “residue”refers to the repeating lactide or glycolide moiety of the polymer. Forexample, if x=0.85 (PLGA=85:15), RMW=69.96. Thus, 1.0 gram of PLGA=85:15contains 0.01429 moles of residues which, on hydrolysis of the polymer,will yield 0.01429 moles of lactic and/or glycolic acid. If, e.g.,calcium carbonate is the buffering agent, and it is desired toneutralize, e.g., 50 mole % of the acids by the reaction

CaCO₃+2HA→CaA₂+H₂O+CO₂

[0061] where A=lactate or glycolate, then the weight of calciumcarbonate needed is (0.25) (0.01429) (100.09)=0.358 gram, and therequired loading is (0.358) (1+0.358) (100)=26.3% by weight.

[0062] Several methods may be used to incorporate the buffer into thepolymer. These methods include solution casting coupled with solventevaporation, dry mixing, incorporating the buffer into a polymer foam,and the polymer melt method.

[0063] Solution casting coupled with solvent evaporation may be usedwith buffers which are either soluble or insoluble in the solvent. Thebioerodible polymer is dissolved in any suitable volatile solvent, suchas acetone, tetrahydrofuran (THF), or methylene chloride. The buffer,which may be soluble or insoluble in this solvent, is added to give thefinal desired ratio of polymer to buffer. If particle size reduction ofthe buffer is necessary, it may be accomplished by ball milling thesuspension of buffer in the polymer solution. In contrast, if the bufferis soluble in the chosen solvent, particle size reduction at any stageis not necessary.

[0064] The suspension or co-solution is cast as a film on a glass orother inert surface, and the solvent is removed by air drying. Residualsolvent remaining in the film may be further removed by subjecting thefilm to vacuum drying at elevated temperatures. As an example, ifcalcium carbonate is to be used as a buffering compound and it isdesired to neutralize 50% of the acid formed by hydrolysis ofPLGA-50:50, the buffer content of the composition should be 27.8%.

[0065] In an exemplary embodiment, to prepare 50 grams of composite,36.1 grams of PLGA-50:50 are dissolved in approximately 250 ml oftetrahydrofuran, and 13.9 grams of calcium carbonate of the desiredparticle size range is added to the solution mixture. After distributingthe calcium carbonate homogeneously by mixing, the suspension is driedto a film as described above.

[0066] The resulting film may be processed by compaction under highpressure, extruded through a die, injection molded, or other methodknown in the art. Further definition of the final shape may beaccomplished at this point by any desirable machining process, such aslathing.

[0067] In the dry-mixing method, a polymer of appropriate particle sizerange is mixed with the buffer, also of chosen particle size range, inproportions to give the desired stoichiometric buffering capacity. Thedry mixture is thoroughly blended by rotating the mixture in a ball milljar from which the grinding balls have been omitted, or other suitablemixing device. The blended mixture may then be processed by compaction,extrusion, injection molding, etc., as described above.

[0068] In the polymer melt method, a known weight of the buffer isincorporated by mixing into a known weight of a suitable melted polymer.A quantity of polymer is heated to a temperature above its meltingpoint, and a suitable buffer is blended into the melted polymer. Theresulting polymer/buffer composite is solidified by cooling, and may beprocessed as described above, or ground and sieved prior to processing.

[0069] In some applications, it may be desirable to protect thebuffering compound, for example, during processing according to the meltmethod, or to make the buffering compound available at the later stagesof polymer degradation. In such cases, it is desirable to coat thebuffering compound particles with a material that degrades at a slowerrate than the material chosen for the fixation devices. Thus, thebuffering compound is exposed only after the body of the device and thecoating material have partially degraded. Exemplary materials used tocoat the buffering compound particles include high molecular weightpoly(L-lactide) or poly(ε-caprolactone).

[0070] The particles of buffering compound may be coated with theprotective material by any method that coats particles, such as spraycoating with a solution of protecting polymer or micro-encapsulation.Alternatively, a chosen protective polymer may be made in a melted stateand buffer particles are added. The melt is cooled and ground and milledto the desired particle size range. Alternatively, the bufferingcompound may be added to a solution of the protective polymer andremoving the solvent by evaporation. The dried mass is compacted in amold under high pressure and grinding or milling the compacted mass tothe appropriate particle size range.

[0071] The resorbable spinal fusion device of the invention optionallyincludes a biological growth factor, e.g., bone morphogenic protein, toenhance bone cell growth. To protect the growth factor and to providefor controlled delivery, the biological growth factor may be itselfcompounded with a resorbable polymer by one of the many techniquesavailable and prepared as a growth factor/polymer composite in pelletform, in small particle form or within the interstices or pores of apolymeric foam or low-density polymer and this polymer/growth factorcomposite deposited into void spaces of the resorbable spinal fusiondevice. Alternatively, the growth factor may simply be directlyincorporated into the component formulation of the resorbable spinalfusion device.

[0072] Active periosteum cells, or other bony cells, may be alsoincorporated into a foam surrounding, or deposited in, the resorbablespinal fusion device so that the cells may facilitate bone cell fusion.To carry out such an incorporation, the periosteum surrounding a humanbone is removed and cultured following standard cell culturingtechniques. The scaffold for such periosteum cell growth is a resorbablepolymer foam or mesh. This scaffolding is prepared by dipping thecompleted device in a polymer/solvent (such as PLGA dissolved in aceticacid). The so-wetted device is then frozen and subsequently freeze-dried(lyophilized) resulting in a foam layer (or coating) of polymersurrounding the device. After the periosteum cells have been grown inthis foam layer, the device is incorporated into the spine for theenhancement of spinal fusion.

[0073] In another embodiment, the resorbable spinal fusion device may beprepared in such a manner as to exhibit a piezoelectric effect. It isknown that oriented (molecularly aligned) biopolymers such as PLGA havepiezoelectric characteristics. In addition, the oriented biopolymerpoly-l-lactic acid (PLLA) has been shown to promote bone wound healing(Shimono et al., In Vivo 10:471-476, 1996 and Ikada et al., J. Biomed,Mater. Res. 30:553-558, 1996). To take advantage of this phenomenon, theresorbable polymer is first aligned, by drawing, for example, such thatall polymer chains are essentially parallel. The spinal fusion device isthen cut from this aligned polymeric material such that the polymerchains are at approximately a 45° angle to the surface of the device,this angle being known to produce the optimal piezoelectric effect.Buffers, reinforcement materials, growth factors, etc., may also beincluded in processing of the spinal fusion device to exhibit thisphenomenon.

[0074] As described by White et al. (Clinical Biomechanics of the Spine,2nd edition, 1990), there are four stages of maturation of thearthrodesis (spinal fusion): I, fibrous healing; II, mixed fibrous andosseous healing; III, immature osseous healing; and IV mature osseoushealing. Stage I requires maximum protection with restricted activityand perhaps a protective orthosis. During stage II relatively lessprotection is required although with restricted activity. During stageIII the patient is allowed normal but nonvigorous activity. In stage IV,maximum healing will be reached. For clinically stable patients thefirst three stages require about six weeks each, and stage IV, a minimumof six weeks. Clinically unstable patients require more time, especiallyfor the first two stages. Thus the goals for duration and strength maybe estimated.

[0075] A prototype device has been prepared for in vitro determinationof weight loss and failure strength as a function of time. Due to theasymmetric design of the IFD, it is not feasible to measure thecompressive modulus over time of the in vitro prototypes. Thisparameter, as well as failure and ultimate strength over time in vitro,has been measured on cylindrical discs of the same overall dimensions.In vitro experiments permit monitoring of the change in molecular weightin time for correlation with the mechanical measurements. Devices aretested for mechanical properties, e.g., compressive strength,compressive modulus, with equipment such as, e.g., the TA-XT2 TextureAnalyzer (Texture Technologies Corporation) or the Instron 8511Servo-Hydraulic System (Instrom Corp.).

[0076] PLGA-85:15 (Resomer RG 858) including reinforcing fibers and HAbuffer was molded at approximately 50° C. under a force of 7-9 tons toform a translucent cylindrical rod 1.6 cm in diameter and 5.0 cm inlength. Devices were then machined to the appropriate final dimensions,as discussed earlier. White and Panjabi (p. 29) report dimensions andstresses to which thoracic vertebrae are subject. The average area ofthe upper and lower end plates of T1 is about 340 mm², and is subject toa loading force of about 2000 N. The compressive strengths of exemplarybuffered and reinforced devices were, in all cases, greater than 13,000N. Thus, the initial strength of these PLGA-85:15 devices is in excessof the stress to which cervical vertebrae will be subject and greateralso than clinical targets of 10,000 N. Devices so made do not fractureat failure but rather irreversibly compress.

[0077]FIG. 7 illustrates this phenomenon. Failure at 13 kN is indicatedby a slowly rising load at displacements greater than about 1.5 mm. Ifthe tested device had failed by fracture, a rapid drop in load wouldhave resulted. The design of the IFD and the PLGA comonomer ratio (i.e.,lactide:glycolide ratio) enable the device to function through the fourstages of healing with progressive loss of mass and strength. Inclinically stable situations, at the end of stage I, the device shouldretain 70-80% of its mechanical strength, and at the end of stage II,50% of its strength should be retained. During stages III and IV,further slow degradation will occur with complete resorption by oneyear.

[0078] Prototype devices have been prepared for feasibility trials withgoats as the animal model. A viable model for testing fusion materialsin the cervical spine is the in vivo goat model. Unlike most quadrupeds,the goat holds its head erect, thus loading the cervical vertebrae in amanner similar to humans. Although there are geometric differences, therelative sizes of the disc and vertebral bodies are similar to those ofthe human. (Pintar et al., Spine 19:2524-2528, 1994; Zdeblick et al.,Spine 17(105):5418-5426, 1992.) The goat is thus the animal model ofchoice for testing the spinal fusion device of the invention.

[0079] The experimental procedure followed in the in vivo goat model isas follows. Anesthetized animals undergo implantation via a surgery tothe anterior cervical spine (Pintar et al., Spine 19:2524-2528, 1994).After exposing the lower 5 cervical segments, discectomy is performed atfour levels. Two resorbable IFD's filled with cancellous bone are placedin two of these spaces, the others receive a piece of tricortical iliacbone graft in place. The bone graft and cancellous bone are harvestedfrom the goat iliac crest through a separate incision over the hip bone.Placement of the IFD or the graft in upper or lower sites is alternatedfor each animal with an intact disc space between implants. Theoperative sites are closed, and the animals allowed to recover.

[0080] At sacrifice, the spinal column of the goat is excised leavingthe intact ligamentous column. The cervical and lumbar sites areseparated and radiographed before mounting for biomechanical (asdescribed above) or histological analyses for resorptive activity andnew bone formation. The fusion rate and biomechanical stiffness areevaluated for spinal units harvested from the goats. Spinal unitsundergo radiographic imaging to assess fusion, biomechanical testing toassess strength, and histological analysis to assess tissue changes. Theresults are compared to conventional graft-based spacers and fusiondevices.

[0081] PLGA implants can be effectively reinforced by the use ofdegradable scaffolds which are molecularly dispersed in the host PLGApolymer. For example, a solid solution containing PLGA, poly(propylenefumarate) (PPF), and vinyl pyrrolidinone(VP) as a crosslinking agent (orother vinyl monomer) may be heated with an initiator (such as benzoylperoxide). The PPF chains are crosslinked by VP to form aninterpenetrating network of crosslinked PPF and PLGA polymer chains.Following heating, further crosslinking is possible using y-irradiation,e.g. 2.5 mrad.

[0082] Several reinforcement techniques described in the literatureinclude self-reinforcement using aligned PLGA fibers (Vainionpaa et al.,Biomaterial 8:46-48, 1987; Pihlajamaki et al., J. Bone and Joint Surgery74:13:853-857, 1992; Ashammakhi et al., J. Biomedical Materials Research29: 687-694, 1995) and reinforcement with calcium phosphate glass fibers(R. A. Casper et al., Polym. Mater. Sci. Eng. 53:497-501, 1985).

[0083] Reinforcement can also be achieved according to the invention bymolding a rod of rectangular or other suitable cross-section thatcontains fibers under tension using the mold and ram assembly of theinvention, as shown in FIGS. 6A-6G. Referring to FIG. 6A, mold cavity 61and ram 62 are rectangular in cross-section in the illustratedembodiment. The mold illustrated is constructed of five plates (frontface plate 63, rear face plate 64, side plates 65 and bottom plate 66),suitably fastened or bonded together. The front and rear face plates 63,64 are machined or otherwise formatted, as will be described below, withkey holes 60 to receive holder assemblies for the reinforcing fibers,which comprise front and rear tension tubes, front and rear tension tubecaps, serrated discs, and a front tension tube threaded nut.

[0084] Referring to FIG. 6B (an edge view of front face plate 63) andFIG. 6C (a plan view of front face plate 63), the inside face 67 ofplate 63 contains a circular recess 68, with associated slots 69. Recess68 adjoins a larger recess 70 that extends to the outside face 71 offront face plate 63. Recess 70 includes associated slots 72. The axisbetween slots 72 is perpendicular to the axis between slots 69. Asmaller diameter recess stop 73 separates recess 68 from recess 70. Rearface plate 64 is similarly configured.

[0085] Referring now also to FIGS. 6D-G, the mold is assembled for useas follows. A disc 75 (FIG. 6D) having serrated slots 76 is threadedwith polymer fibers 88, which are distributed throughout the serratedslots. The distribution of the fibers is spatially maintained by theserrations. Referring also to FIG. 6G, discs 75 with fibers in place aremounted in recesses 68 in the front and rear face plates 63, 64 of theassembled mold. Orientation of discs 75 is maintained by vanes 77 on thesides of the discs, which fit into slots 69. Alternatively, discs 75 maybe mounted first in face plates 63, 64 and threaded in place. Theprotruding fiber bundles are then threaded through front and reartension tube assemblies 78, 79, which are positioned in recesses 70 inthe front and rear face plates 63, 64, respectively. Tension tubeassemblies 78, 79 consist of tension tubes 80, each having vanes 82which fit into slots 72 in the front and rear face plate recesses 70,respectively, thus maintaining the orientation of the tubes. The tensiontubes are closed with caps 83 to complete assemblies 78, 79. The fiberbundles are threaded additionally through holes 84 in the front and reartension tube caps, as they exit the tension tubes. Holes 84 areoff-center and below the axis of the tension tubes. This configurationholds the fibers against the serrations of the discs. Outside the caps,the fibers may be knotted to keep them from slipping back through theholes. Other methods of anchoring the fibers may be used. For example, abead of cement (such as epoxy or cyanoacrylate adhesives) may be builtup on the outside of the caps to keep the fibers from slipping through.Also referring to FIGS. 6E and 6F, it can be seen that the tension tube80 of front tension tube assembly 78 is exteriorly threaded 85 along itslength and equipped with a nut 86 which, when tightened against the faceplate, pulls the tension tube partially out of the face plate, thusputting the fibers under tension.

[0086] To prepare a reinforced resorbable spinal fusion device, moldcavity 61 of the assembled mold is then filled with the appropriatepowdered formulation. The powdered formulation may be evenly distributedamong the fibers by placing the mold on a vibrator. Ram 62 is put inplace, in the opening of the mold, and pressure is exerted. The mold maybe heated externally with heating tapes, or it may be so machined as tohave recesses for cartridge heaters. When the molding process iscomplete, the tension on the reinforcing fibers is released, and thecompleted device is removed from the mold.

[0087] While the present invention has been described in conjunctionwith a preferred embodiment, one of ordinary skill, after reading theforegoing specification, will be able to effect various changes,substitutions of equivalents, and other alterations to the compositionsand methods set forth herein. It is therefore intended that theprotection granted by Letters Patent hereon be limited only by thedefinitions contained in the appended claims and equivalents thereof.

What is claimed is:
 1. A resorbable interbody spinal fusion device forspinal fixation, said device comprising 25-100% resorbable material. 2.The resorbable interbody spinal fusion device of claim 1 , furthercomprising one or more void spaces therein.
 3. The resorbable interbodyspinal fusion device of claim 2 , wherein one of said one or more voidspaces contains a grafting material for facilitating bony developmentand/or spinal fusion.
 4. The resorbable interbody spinal fusion deviceof claim 3 , wherein said grafting material is an autologous graftingmaterial.
 5. The resorbable interbody spinal fusion device of claim 1 ,wherein said device is shaped substantially as a tapered wedge or cone.6. The resorbable interbody spinal fusion device of claim 1 , whereinsaid device is shaped substantially as a threaded screw.
 7. Theresorbable interbody spinal fusion device of claim 1 , wherein saiddevice is shaped substantially as a threaded rod of cruciformconfiguration.
 8. The resorbable interbody spinal fusion device of claim5 , further comprising at least one serrated or threaded outer face. 9.The resorbable interbody spinal fusion device of claim 1 , wherein saidresorbable material is a polymer producing acidic products or lowmolecular weight resorbable fragments upon hydrolytic degradation. 10.The resorbable interbody spinal fusion device of claim 9 , wherein saidresorbable material further comprises a buffering or neutralizing agentin sufficiently high concentration to moderate the rate of change of pHof said resorbable material during resorption.
 11. The resorbableinterbody spinal fusion device of claim 1 , wherein said resorbablematerial is a polymer selected from the group consisting ofpolydioxanone, poly(ε-caprolactone), polyanhydride, polyester,copoly(ether-ester), polyamide, polylactone, poly(propylene fumarate),and combinations thereof.
 12. The resorbable interbody spinal fusiondevice of claim 11 , wherein said bioerodible polymer comprisespoly(lactide-co-glycolide) with a lactide to glycolide ratio in therange of 0:100% to 100:0% inclusive.
 13. The resorbable interbody spinalfusion device of claim 10 , wherein said buffering or neutralizing agentis a polymer comprising at least one basic group.
 14. The resorbableinterbody spinal fusion device of claim 13 , wherein said polymercomprising at least one basic group is selected from the groupconsisting of polyamines, polyesters, vinyl polymers, and copolymers ofacrylic acid.
 15. The resorbable interbody spinal fusion device of claim10 , wherein said buffering or neutralizing agent is a compound that, onexposure to water, hydrolyzes to form a base.
 16. The resorbableinterbody spinal fusion device of claim 10 , wherein said buffering orneutralizing agent is selected from the group consisting of carbonates,phosphates, acetates, succinates and citrates.
 17. The resorbableinterbody spinal fusion device of claim 1 wherein said resorbablematerial further comprises reinforcing fibers.
 18. The resorbableinterbody spinal fusion device of claim 17 , wherein said reinforcingfibers are made of said resorbable material.
 19. The resorbableinterbody spinal fusion device of claim 10 , wherein said resorbablematerial further comprises reinforcing fibers.
 20. The resorbableinterbody spinal fusion device of claim 19 , wherein said reinforcingfibers are made of said buffering or neutralizing agent.
 21. A method ofmaking a resorbable interbody spinal fusion device, comprising the stepsof: providing a mold for said resorbable interbody spinal fusion device;orienting reinforcing fibers under tension in said mold; introducing aresorbable material into said mold; molding said resorbable mater ialunder pressure; and releasing tension on said reinforcing fibers priorto removing said device from said mold.
 22. The method of claim 21wherein said resorbable reinforcing fibers are made of the same materialas said resorbable interbody material.
 23. The method of claim 21wherein said resorbable reinforcing fibers do not contain a buffer. 24.The resorbable interbody spinal fusion device of claim 10 wherein saidbuffering or neutralizing agent is selected from the group consisting ofcompounds wherein the pKa of the conjugate acids of said compounds isgreater than the pKa of acids produced by hydrolysis of the polymer(s)from which said device is prepared.
 25. The resorbable interbody spinalfusion device of claim 1 , wherein said device is fabricated from atleast two resorbable polymers.
 26. The resorbable interbody spinalfusion device of claim 25 , wherein one of said resorbable polymers ispoly (propylene fumarate).
 27. The resorbable interbody spinal fusiondevice of claim 25 , wherein one of said resorbable polymers has beencross-linked in the presence of a crosslinking agent and an initiator,whereby said crosslinked resorbable polymer forms a reinforcinginterpenetrating network.
 28. The resorbable interbody spinal fusiondevice of claim 25 , wherein said crosslinking agent is vinylpyrrolidone.
 29. The resorbable interbody spinal fusion device of claim25 , wherein said initiator is benzoyl peroxide.
 30. The resorbableinterbody spinal fusion device of claim 1 , wherein said device isfabricated from a polymer wherein molecular chains of said polymer havebeen aligned to be essentially parallel.
 31. The resorbable interbodyspinal fusion device of claim 30 , wherein said device has been cut suchthat the aligned polymer molecular chains are at approximately a 45°angle to a surface of said device.
 32. A resorbable interbody spinalfusion device, wherein said device is substantially manufactured from aresorbable material poly(d,l-lactide-co-glycolide), said device furthercomprising a buffering or neutralizing agent wherein said buffering orneutralizing agent is hydroxyapatite, and wherein said device furthercomprises one or more void spaces therein.
 33. A resorbable interbodyspinal fusion device for spinal fixation, said device comprising 25-100%resorbable material, said device further comprising a buffering orneutralizing agent wherein said buffering or neutralizing agent ishydroxyapatite, and wherein said device further comprises one or morevoid spaces therein.
 34. A resorbable interbody spinal fusion device forspinal fixation, said device comprising 25-100% resorbable material,said device further comprising a buffering or neutralizing agent whereinsaid buffering or neutralizing agent is hydroxyapatite.